Approximately a third of Americans between 20 and 70 years old are considered obese and approximately half of the American population in this age category are considered to be overweight. Obesity is also considered to be an increasing problem in other industrialised countries and in emergent countries where a large amount of people are used to calorie-rich diets influenced by the West. It has been estimated that obesity contributes to up to 50% of chronic diseases in western societies, and is responsible for approximately el 70% of foreseeable deaths in the United States.
Obesity and the disorders it causes, pose serious health problems that are frequent in the United States and throughout the world. Obesity of the abdominal part of the body is the most important known risk factor of Type 2 mellitus diabetes, and represents an important risk factor in cardiovascular diseaeses. Obesity is a recognised risk factor for hypertension, arteriosclerosis, congestive cardiac insufficiency, cerebrovascular accident, cholecystitis, osteoarthritis, sleep apnea syndrome, reproduction disorders such as polycystic ovarian syndrome, breast, prostate and colon cancer, and it is also a recognised risk factor or greater incidences of general anaesthetia complications. Also, it includes a serious risk of comorbility because of the affections described above and for alterations such as infections, varicose veins, Acantosis nigricans, eczemas, exercise intolerance, insulin resistance, hypertension, hypercholesterolemia, gallstones, orthopedic injuries and thromboembolic diseases. Obesity is also a risk factor of the group of diseases called “insulin resistance syndrome” or “X syndrome”.
The medical care costs associated with obesity are substantial. As a result of these factors, the development of compositions for managing to lose weight is a subject of significant commercial interest.
Some weight control approaches include appetite suppressors, reduced calorie diets, exercise programmes, surgical procedures and the like. A variety of weight controlling compositions have been developed; the desired characteristics for these products include the lack of undesirable side effects, high efficiency, convenient dosage rates, and low cost. The drugs developed for treating obesity can have undesirable side effects, are only be available under medical supervision, and can be relatively expensive. Other products such as those with a high fibre content can require large inconvenient doses in order to be effective.
One method of inhibiting the digestion and/or metabolism of lipids in the diet has been to administer non-absorbible materials that are apt for joining up with the lipds or kidnapping them. Another approach to inhibiting digestion and/or the metabolism of dietic lipids is to use compounds that inhibit the activity of certain enzymes that are necessary for lipid digestion. Polymers that inhibit the action of pancreatic lipase are described in U.S. Pat. No. 3,923,976.
Other lipase inhibitors include lipstatin and orlistat. The latter is also known as (−) tetrahydrolipstatin or THL, and it is a derivative of a natural product excreted by Streptomyces toxytricini. It has been discovered that this class of compounds have both in vitro and in vivo activity against various lipases, such as lingual lipase, pancreatic lipase, gastric lipase, and carboxyl ester lipase.
The (−) tetrahydrolipstatin or orlistat (96829-58-2) defined as an inhibitor of the pancreatic lipase and anti-obesity agent (Merck Index XIII Edition) has been mentioned in several patents, including, European patent EP 129 748 (U.S. Pat. No. 4,598,089/1986) granted in the name of Hoffman La Roche, equivalent to Argentinian patent No AR 233.709; U.S. Pat. No. 6,004,996 equivalent to Argentinan patent AR 10.704 B2; and others.
The therapeutic effect of orlistat occurs in the gastric cavity and in the small intestine through the formation of a covalent link in the active site of the serine in gastric and pancreatic lipases, which blocks the hydrolisis of the easily absorbible fats or free fatty acids and monoglycerides.
It has been proved that the absorption of orlistat is minimum, and that the effect is local and non-systemic.
A dosis of 120 mg of orlistat with every main meal, including breakfast, has been recommended.
It has also been recommended to associate it with a diet that provides less than 30% of the total calories originating from fats, in order to reduce the adverse gastro-intestinal effects.
The adverse gastro-intestinal effects observed are associated with the capacity of the (−) tetrahydrolipstatin to prevent the absorption of fats. These particularly include: fat excrement and fecal incontinence associated with the fat content intake.
Such secondary effects frequently lead to the patient suspending the treatment. Particularly when the pharmaceutical form cannot be fractioned and the doctor is inhibited to offer another more flexible alternative dosis.
Since the discovery of orlistat, there has only been one oral pharmaceutical form, i.e.: capsules, and one commercial concentration of 120 mg available for its therapeutical application in human medicine. During 2007, the FDA authorised the first pharmaceutical product also in capsules, with its composition including 60 mg of orlistat, and it represents an important advance in flexibilising the dosis that each patient needs according to their situation and eating habits. In 2009, orlistat 60 mg in capsules was also authorised as OTC products.
Producing oral pharmaceutical forms that comprise orlistat in the form of pellets has proved to not be easy, and this is highlighted in technical literature. Only capsules containing 120 or 60 mg of orlistat exist. This circumstance can also limit the dosage flexibility that certain patients may need.
Technically the literature mentions some features of (−) tetrahydrolipstatin that create practical disadvantages for preparing other oral pharmaceutical forms:                a) (−) Tetrahydrolipstatin is a substance that has a low melting point: 43° C. (Index Merck XIII Edition).        b) It is susceptible to hydrolisis and thermal degradation. Particularly in a wet environment and at a temperature above 35° C., and inclusive in a dry environment (U.S. Pat. No. 6,004,996).        c) Document U.S. Pat. No. 6,004,996 highlights that tablets or capsules cannot be formed easily using the conventional wet granulating method because of adhesion problems during the preparation of the tablet or during encapsulation.        
Consequently, the technical solutions have been aimed preferably at specifically preparing capsules. U.S. Pat. No. 6,004,996 describes the preparation of granules or pellets containing orlistat, together with other acceptable ingredients for obtaining particules between 0.25 and 2 mm that are useful for preparing capsules.
The described alternatives make it possible to overcome the problem of the stability of orlistat. However, the following is observed:                i) obtaining pellets using the method described in document U.S. Pat. No. 6,004,996 requires 7 operations and a drying stage on a fluid bed (Aeromatic MP-I) with an air inlet at a temperature that must be below 35° C.        ii) it only allows a single dosis capasule type pharmaceutical composition to be prepared, with a low dosage flexibility for the patient and the prescribing doctor.        iii) preparing the pellets involves an industrial method that implies using various pieces of specific equipment that are different from those normally used for preparing pharmaceutical forms.        iv) since preparing pellets requires various stages and special equipment, it incurrs an extra cost in addition to the industrial preparation of the pharmaceutical form.        
Another approach to trying to reduce the drawbacks of the art is described in U.S. Pat. No. 6,703,369 (Sep. 3, 2004) granted to Hoffmann La Roche (equivalent to Argentinian application AR 025 609 A1 (Apr. 12, 2002)), wherein a pharmaceutical composition is provided that comprises orlistat and at least one polyol fatty acid ester that has a melting point above 37° C. and wherein the fatty acid has twelve or more atoms.
The composition comprises at least one heavy acid ester of a polyalcohol corresponding to the group Trilaurin (PF 46-47° C.), Trimyristin (PF 56-57° C.), Tripalmitin (PF 68° C.), Triestearin (PF 71-73° C.), or a monoglyceride such as Monolaurin (PF 63° C.), Monomyristin (PF 69-70° C.), Monopalmitin (PF 63-68° C.).
Owing to the nature of the components mentioned, the preparation of the compositions claimed requires, where appropriate, the following type of operations:                Heating to 57-63° C.        Cooling subsequently to room temperature.        Heating to 39° C. up to 4 hours        Operating in an inert environment.        Cold grinding using dry ice or nitrogen (at −80° C.)        
In other words, several stages require high temperatures over 50° C. However, according to the literature the contents disclosed by the same authors of this patent, orlistat undergoes hydrolitic and thermal degrading, over de 35° C. (U.S. Pat. No. 6,004,996; Stalder Henri, Schneider Pierre, Gottfried Oesterhelt; “Tetrahydrolipstatin: Thermal and Hydrolytic Degradation”, Helvetica Chimica Acta; 73 (1990); pages 1022-1035).
Therefore, there is still the need to prepare a pharmaceutical composition for treating obesity, whereby it it possible to regulate the administration dosis of orlistat and which also is prepared by a simple and economic method without generating losses through degradation of the active orlistat compound.